The goals of this research are the development of more accurate methods for molecular simulations of solvated proteins, the construction of multiscale kinetic network models which fully exploit this information, and the application of these new computational tools to forefront problems in structural biology and molecular biophysics. These problems include: (a) protein-ligand binding, both thermodynamics and kinetics;and (b) characterizing the landscapes for protein folding and functional transitions in the native state, with emphasis on mapping the diversity of pathways for folding and binding and their corresponding fluxes. These projects will build on the substantial progress made during the current grant period on the development of state-of-the-art methods for molecular simulations of proteins, and forefront applications which are best suited to investigation using all atom and multiscale kinetic network models. PUBLIC HEALTH RELEVANCE: The goals of this research include the development of accurate methods for structure based drug design using innovative molecular simulations. The target systems for drug design include two human immune-deficiency virus (HIV) proteins - Reverse Transcriptase (RT) and Protease.